Details
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | eaay4458 |
| Seitenumfang | 15 |
| Fachzeitschrift | Science advances |
| Jahrgang | 6 |
| Ausgabenummer | 5 |
| Frühes Online-Datum | 29 Jan. 2020 |
| Publikationsstatus | Veröffentlicht - 31 Jan. 2020 |
Abstract
In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine-based inhibitory motif (ITIM) and immune receptor tyrosine-based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2-PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.
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in: Science advances, Jahrgang 6, Nr. 5, eaay4458, 31.01.2020.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - Molecular mechanism of SHP2 activation by PD-1 stimulation
AU - Marasco, M.
AU - Berteotti, A.
AU - Weyershaeuser, J.
AU - Thorausch, N.
AU - Sikorska, J.
AU - Krausze, J.
AU - Brandt, H. J.
AU - Kirkpatrick, J.
AU - Rios, P.
AU - Schamel, W. W.
AU - Köhn, M.
AU - Carlomagno, T.
N1 - Funding Information: M.M. was supported by a fellowship from the Hannover School for Biomolecular Drug Research and was a member of the Hannover Biomedical Research School (HBRS) and the MD/PhD program "Molecular Medicine". A.B. thanks the EMBL and Marie Curie actions EMBL interdisciplinary postdoctoral program (EIPOD) for a fellowship. This work was funded by the German Science Foundation DFG (grant CA 294/20-1, BIOSS EXC 294, and CIBSS EXC-2189-project ID 390939984).
PY - 2020/1/31
Y1 - 2020/1/31
N2 - In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine-based inhibitory motif (ITIM) and immune receptor tyrosine-based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2-PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.
AB - In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine-based inhibitory motif (ITIM) and immune receptor tyrosine-based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2-PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.
UR - http://www.scopus.com/inward/record.url?scp=85078977696&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aay4458
DO - 10.1126/sciadv.aay4458
M3 - Article
C2 - 32064351
AN - SCOPUS:85078977696
VL - 6
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 5
M1 - eaay4458
ER -